Pyrazolo [1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylic acid heterocyclic derivatives

ABSTRACT

New derivatives of pyrazolo[1,5-a]pyrido[3,2-e]-pyrimidine-7-carboxylic acid have the general formula ##STR1## The new compounds are useful as central nervous system depressants and as anti-inflammatory agents.

This application is a division of application Ser. No. 630,120, filedNov. 7, 1975 now Pat. No. 4,026,893.

SUMMARY OF THE INVENTION

This invention relates to new derivatives ofpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7carboxylic acids and saltsthereof. These new compounds have the general formula ##STR2##

The symbols have the following meanings in formula I and throughout thisspecification:

R, r¹ and R³ each is hydrogen or lower alkyl;

R² is hydrogen, lower alkyl or phenyl;

R⁴ is hydroxy, halogen, lower alkoxy, di-lower alkylamino-lower alkoxyor a basic acyclic or cyclic amino group ##STR3##

DETAILED DESCRIPTION OF THE INVENTION

The lower alkyl groups are straight or branched chain hydrocarbon groupshaving up to seven carbon atoms in the chain, e.g., methyl, ethyl,propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl, heptyl, etc.The C₁ -C₄ lower alkyl groups and especially C₁ -C₂ groups arepreferred.

The lower alkoxy groups are similar, including lower alkyl groups of thekind described above attached to the oxygen. The C₁ -C₄ and C₁ -C₂groups similarly constitute preferred and especially preferred groups,respectively.

The halogens are the four common halogens, but chlorine and bromine arepreferred especially the first.

The basic amino group ##STR4## is an acyclic amino group in which R⁵ andR⁶ each is hydrogen, lower alkyl, phenyl, substituted phenyl (whereinthe phenyl substituent is one or two halogen or trifluoromethyl groups,preferably only one), phenyl-lower alkylene or di-lower alkylamino-loweralkylene (the lower alkyl and lower alkylene groups being similar to thelower alkyl groups described above, with the C₁ -C₄ and C₁ -C₂ groupsconstituting preferred and especially preferred members, respectively).Preferably only one of R⁵ or R⁶ is phenyl, substituted phenyl,phenyl-lower alkylene or di-lower alkylamino-lower alkylene, the otherbeing hydrogen. Such acyclic amino groups include, for example, amino,lower alkylamino (e.g., methylamino, ethylamino, propylamino,isopropylamino, etc.), di-lower alkylamino (e.g., dimethylamino,diethylamino, dipropylamino, methylethylamino, etc.), anilino,(o-trifluoromethyl)anilino, o-chlorophenylamino, p-bromophenylamino,benzylamino, phenethylamino, dimethylaminomethylamino,dimethylaminoethylamino, (methylethyl)aminomethylamino,dipropylaminoethylamino, etc.

The di-lower alkylamino-lower alkoxy groups represented by R⁴ aresimilar to the groups referred to in the preceding sentence except forthe linking oxygen in place of the nitrogen. Such groups having up tofour carbons in each alkyl group are preferred. Examples includedimethylaminomethoxy, diethylaminomethoxy, diethylaminoethoxy,dimethylaminopropoxy and the like.

The basic amino group ##STR5## also represents a heterocyclic radicalwherein R⁵ and R⁶ join to complete one of the groups aziridinyl,pyrrolidino, piperidino, pyrazolyl or piperazinyl. The heterocyclic(preferably piperidino and piperazinyl) can also bear as a substituent ahydroxy-lower alkyl group or one or two lower alkyl groups (preferablyin a para-position, e.g., 4-methylpiperazinyl,4-hydroxyethylpiperazinyl, 4-methylpiperidino).

The products of the examples (especially Examples 1 to 9) are preferredembodiments.

Especially preferred compounds of Formula I are those wherein

R is ethyl;

R¹ is hydrogen or methyl, especially hydrogen;

R² is hydrogen or lower alkyl, especially methyl;

R³ is hydrogen or lower alkyl, especially methyl;

R⁴ is lower alkylamino, especially n-butylamino or sec. butylamino.

The compounds of formula I are produced from a7-aminopyrazolo[1,5-a]pyrimidine of the formula ##STR6## [producedanalogous to the procedure described in J. Het. Chem. 11, 423 (1974)]which is made to react with an alkoxymethylenemalonic acid ester of theformula ##STR7## by heating at a temperature of about 140° C. Theresulting compound of the formula is cyclized in an inert organicsolvent like diphenylether at about 230°-260° C., while distilling offthe alcohol formed producing a compound of the formula ##STR8##

Compounds of the formula ##STR9## wherein X is halogen (preferablychlorine or bromine) are new intermediates, produced by reacting acompound of formula Ia with an appropriate acid halide, like phosphorusoxychloride or bromide.

Compounds of the formula ##STR10## with a lower alkoxy group in the6-position are now obtained by reaction of a compound of formula Ib withan alkali metal alcoholate, like sodium methoxide, potassium ethoxide orthe like.

Compounds of the formula ##STR11## are obtained by reacting a compoundof formula Ic or Ib with the appropriate amine of the formula ##STR12##at elevated temperatures. Sometimes it is advantageous to use anautoclave.

The new compounds of formula I form salts which are also part of thisinvention. The salts include acid addition salts, particularly thenon-toxic, physiologically acceptable members. These salts are formed byreaction with one or more equivalents of any of a variety of inorganicand organic acids, especially the strong acids, providing acid additionsalts including, for example, hydrohalides (especially hydrochloride andhydrobromide), sulfate, nitrate, borate, phosphate, oxalate, tartrate,maleate, citrate, acetate, ascorbate, succinate or aryl- oralkanesulfonates like benzenesulfonate, methanesulfonate,cyclohexanesulfamate and toluenesulfonate. The acid addition saltsfrequently provide a convenient means for isolating the product, e.g.,by forming and precipitating a salt (which is not necessarily non-toxic)in an appropriate medium in which the salt is insoluble, then afterseparation of the salt, neutralizing with a base such as bariumhydroxide or sodium hydroxide, to obtain the free base of formula I.Other salts can then be formed from the free base by reaction with oneor more equivalents of acid containing the desired anion.

Certain members, i.e., wherein R is hydrogen, form salts with metals,e.g., alkali metals like sodium, alkaline earth metals like calcium andmagnesium, etc. These salts are useful to form soluble derivatives or asintermediates. They are also within the scope of the invention.

Additional experimental details are found in the examples.

The new compounds of this invention are psychotropic agents havingcentral nervous depressant activity and can be used as ataractic agentsfor the relief of anxiety and tension states, for example, in mice,cats, rats, dogs and other mammalian species. For this purpose acompound or mixture of compounds of formula I, or non-toxic,physiologically acceptable salt thereof, is preferably administeredorally, but parenteral routes such as subcutaneously, intramuscularly,intravenously or intraperitoneally in the described dosages, can also beemployed. A single dose, or preferably 2 to 4 divided daily doses,provided on a basis of about 1 to 50 mg. per kilogram per day,preferably about 5 to 15 mg. per kilogram per day, is appropriate.

The new compounds of this invention also have anti-inflammatoryproperties and are useful as anti-inflammatory agents, for example, toreduce local inflammatory conditions such as those of an edematousnature or resulting from proliferation of connective tissue in variousmammalian species such as rats, dogs and the like when given orally orparenterally in dosages of about 5 to 50 mg/kg/day, preferably 5 to 25mg/kg/day, in single or 2 to 4 divided doses, as indicated by thecarageenan edema assay in rats or delayed hypersensitivity skin reactiontest.

The compounds of the invention can be utilized by formulating incompositions such as tablets, capsules or elixirs for oraladministration or in sterile solutions or suspensions for parenteraladministration. About 10 to 250 mg. of a compound or mixture ofcompounds of formula I or physiologically acceptable salt (preferablyacid addition salt) is compounded with a physiologically acceptablevehicle, carrier, excipient, binder, preservative, stabilizer, flavor,etc., in a unit dosage form as called for by accepted pharmaceuticalpractice. The amount of active substance in these compositions orpreparations is such that a suitable dosage in the range indicated isobtained.

Illustrative of the adjuvants which may be incorporated in tablets,capsules and the like are the following: a binder such as gumtragacanth, acacia, corn starch or gelatin; an excipient such asdicalcium phosphate; a disintegrating agent such as corn starch, potatostarch, alginic acid and the like; a lubricant such as magnesiumstearate; a sweetening agent such as sucrose, lactose or saccharin; aflavoring agent such as peppermint, oil of wintergreen or cherry. Whenthe dosage unit form is a capsule, it may contain in addition tomaterials of the above type a liquid carrier such as a fatty oil.Various other materials may be present as coatings or to otherwisemodify the physical form of the dosage unit. For instance, tablets orcapsules may be coated with shellac, sugar or both. A syrup or elixirmay contain the active compound, sucrose as a sweetening agent, methyland propyl parabens as preservatives, a dye and a flavoring such ascherry or orange flavor. Of course, any material used in preparing thedosage unit should be pharmaceutically pure and substantially non-toxicin the amounts employed.

For topical administration as an anti-inflammatory agent, a conventionallotion, ointment, or cream containing about 0.1 to 3 percent by weightof a compound of formula I or its salt is formulated.

The following examples are illustrative of the invention and constitutepreferred embodiments. They also serve as models for the preparation ofother members of the group which can be produced by suitablesubstitution of starting materials. All temperatures are in degreescelsius.

EXAMPLE 12,5-Dimethyl-6-(4-methyl-1-piperazinyl)pyrazolo[1,5-a]pyrido-[3,2-e]pyrimidine-7-carboxylicacid, ethyl ester a.[[(2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-yl)amino]-methylene]propanedioicacid, ethyl ester

168 g. of 2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-amine (1 mol.) and 216g. of ethoxymethylenemalonic acid diethyl ester (1 mol.) are heatedtogether with stirring at 140° until the theoretical amount of alcoholhas been distilled off (about 1 hour). The mixture is cooled to roomtemperature and the product[[(2,5-dimethylpyrazolo-[1,5-a]pyrimidin-7-yl)amino]methylene]propanedioicacid, ethyl ester is recrystallized from ethyl acetate, yield 280 g.(84%), m.p. 130°-132°.

b.6-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyrido[3,2-e]-pyrimidine-7-carboxylicacid, ethyl ester

33.2 g. of[[(2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-yl)amino]methylene]propanedioicacid, ethyl ester (0.1 mol.) are heated in 100 ml. of diphenyl ether at240° for 7 minutes. The mixture is cooled rapidly and 100 ml. of diethylether are added. The product,6-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylicacid, ethyl ester, precipitates and is filtered off, yield 20.1 g.(75%), m.p. 207°-208° (methanol).

c. 6-chloro-2,5-dimethylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylic acid, ethyl ester

13.4 g. of6-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylicacid, ethyl ester (0.05 mol.) and 100 ml. of phosphorous oxychloride arerefluxed with stirring for 5 hours. The excess of chlorinating agent isdistilled off and the dark residue is poured into ice-water.6-Chloro-2,5-dimethylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine7-carboxylicacid, ethyl ester precipitates, yield 6.4 g. (42%), m.p. 143°-145°(ethyl acetate). d.2,5-dimethyl-6-(4-methyl-1-piperazinyl)pyrazolo1,5-a]-pyrido[3,2-e]pyrimidine-7-carboxylicacid, ethyl ester

3.04 g. of6-chloro-2,5-dimethylpyrazolo[1,5-a]-pyrido[3,2-e]pyrimidine-7-carboxylicacid, ethyl ester (0.01 mol.) and 10 ml. of N-methylpiperazine areheated at reflux temperature for 5 minutes. The excess N-methylpiperazine is removed in vacuo and the residue is treated with water.The product,2,5-dimethyl-6-(4-methyl-1-piperazinyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylicacid, ethyl ester, crystallizes and is filtered off, yield 3.1 g. (85%),m.p. 158°-159°.

EXAMPLE 2 6-Hydroxy-5-methylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylic acid, ethyl ester a.[[(5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino] methylene]propanedioicacid, ethyl ester

By substituting 5-methylpyrazolo[1,5-a]pyrimidin-7-amine for the2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-amine in the procedure of Example1a, 5-methylpyrazolo[1,5-a]-pyrimidin-7-yl)amino]methylene]propanedioicacid, ethyl ester is obtained, yield 80%, m.p. 98°-100° (methanol).

b.[[6-hydroxy-5-methylpyrazolo[1,5-a]pyrido]3,2-e]pyrimidine-7-carboxylicacid, ethyl ester

By substituting the product of part a for the[[(2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-yl)amino]methylene]-propanedioicacid ethyl ester in the procedure of Example 1b,6-hydroxy-5-methylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylicacid, ethyl ester is obtained, yield 73%, m.p. 190°-192° (methanol).

EXAMPLE 32,5-Dimethyl-6-(1-piperidinyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylicacid, ethyl ester

When6-chloro-2,5-dimethylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylicacid, ethyl ester of Example 1c is treated with piperidine according tothe procedure of Example 1d,2,5-dimethyl-6-(1-piperidinyl)-pyrazole[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylicacid, ethyl ester is obtained, yield 88%, m.p. 161°-163° (ethylacetate).

EXAMPLE 46-[[3-(Dimethylamino)propyl]amino]amino]-2,5-dimethylpyrazolo-[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylicacid, ethyl ester

When6-chloro-2,5-dimethylpyrazolo[1,5-a]pyrido-[3,2-e]pyrimidine-7-carboxylicacid, ethyl ester of Example 1c is treated with(3-dimethylamino)propylamine,6-[[3-(dimethylamino)propyl]amino]-2,5-dimethylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylicacid, ethyl ester is obtained, yield 76%, m.p. 73°-75° (ethyl acetate).

EXAMPLE 52,5-Dimethyl-6-[(1-methylpropyl)amino]pyrazolo[1,5-a]-pyrido[3,2-e]pyrimidine-7-carboxylicacid, ethyl ester

3.0 g. of6-chloro-2,5-dimethylpyrazolo[1,5-a]-pyrido[3,2-e]pyrimidine-7-carboxylicacid, ethyl ester of Example 1c (0.01 mol.) are dissolved in 20 ml. ofalcohol. 2.1 g. of sec. butylamine (0.03 mol.) are added and the mixtureis refluxed with stirring for 1 hour. The solvent and excess amine isremoved in vacuo and the crystalline residue is treated with water andfiltered off to obtain2,5-dimethyl-6-[(1-methylpropyl)amino]pyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylicacid, ethyl ester, yield 3.1 g. (91%), m.p. 113°-115° (ethyl acetate).

EXAMPLE 66-(n-Butylamino)-2,5-dimethylpyrazolo[1,5-a]pyrido[3,2-e]-pyrimidine-7-carboxylicacid, ethyl ester

By substituting n-butylamine for the sec. butylamine in the procedure ofExample5,6-(n-butylamino)-2,5-dimethylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylicacid, ethyl ester is obtained, yield 89%, m.p. 114°-116° (ethylacetate).

By treating this product with a slight excess of dry ethanolic potassiumhydroxide and refluxing for 3 hours under argon, the potassium salt isobtained. The addition of dilute hydrochloric acid and evaporation ofthe solvent yields the free carboxylic acid.

EXAMPLE 72,5-Dimethyl-6-(methylamino)pyrazolo[1,5-a]pyrido[3,2-e]-pyrimidine-7-carboxylicacid, ethyl ester

By substituting methylamine for the sec. butylamine in the procedure ofExample 5,2,5-dimethyl-6-(methylamino)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylicacid, ethyl ester is obtained, yield 78%, m.p. 208°-210° (methanol).

EXAMPLE 82,5-Dimethyl-6-(3-methyl)butoxypyrazolo[1,5-a]pyrido[3,2-e]-pyrimidine-7-carboxylicacid, ethyl ester

0.97 g. of 3-methyl-1-butanol (0.011 mol.) are dissolved in 50 ml. ofdry benzene. After addition of 0.27 g. of sodium hydride, the mixture isrefluxed for 5 hours. After this time, 3.0 g. of6-chloro-2,5-dimethylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylicacid, ethyl ester are added and heating is continued for 3 hours. Thesolvent is removed in vacuo, the residue is treated with dilute 10%acetic acid and extracted twice with 50 ml. portions of ether. The etherlayers are combined, washed with sodium carbonate and then with water,and dried over sodium sulfate. The solution is filtered and evaporatedto dryness. The residue is recrystallized from ligroin, yield 1.1 g.(31%), m.p. 75°-77°.

EXAMPLE 92,5-Dimethyl-6-(3-dimethylamino)propoxypyrazolo[1,5-a]pyrido-[3,2-e]pyrimidine-7-carboxylicacid, ethyl ester

By substituting (3-dimethylamino)propan-1-ol for the 3-methyl-1-butanolin the procedure of Example 8,2,5-dimethyl-6-(3-dimethylamino)propoxypyrazolo[1,5-a]-pyrido[3,2-e]pyrimidine-7-carboxylicacid, ethyl ester is obtained, yield 18%, m.p. 43°-45° (ligroin).

EXAMPLE 106-Chloro-5-methylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylicacid, ethyl ester

By substituting the product of Example 2 for the6-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylicacid in the procedure of Example 1c,6-chloro-5-methylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylicacid, ethyl ester is obtained.

EXAMPLE 116-Amino-5-methylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylicacid, ethyl ester

By treating the product of Example 10 with ammonia according to theprocedure of Example 5,6-amino-5-methyl-pyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylicacid, ethyl ester is obtained. Treatment of this product with ethanolichydrochloric acid yields the hydrochloride salt.

The following additional products are produced by the procedure ofExample 1 by substituting the reactant with the desired substituent inpart a, c, or d and the procedure of Example 8 for compounds wherein R₄has a lower alkoxy chain or Example 6 for the free carboxylic acid orsalt:

    ______________________________________                                         ##STR13##                                                                    Ex.  R      R.sup.1                                                                              R.sup.2                                                                              R.sup.3                                                                            R.sup.4                                        ______________________________________                                        12   CH.sub.3                                                                             C.sub.2 H.sub.5                                                                      H      CH.sub.3                                                                           N(C.sub.2 H.sub.5).sub.2                       13   H      CH.sub.3                                                                             H      H    NHC.sub.2 H.sub.5                              14   C.sub.2 H.sub.5                                                                      CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                           NHbutyl                                        15   C.sub.2 H.sub.5                                                                      H                                                                                     ##STR14##                                                                           CH.sub.3                                                                           OH                                             16   C.sub.2 H.sub.5                                                                      H                                                                                     ##STR15##                                                                           CH.sub.3                                                                           Cl                                             17   C.sub.2 H.sub.5                                                                      H                                                                                     ##STR16##                                                                           CH.sub.3                                                                            ##STR17##                                     18   C.sub.3 H.sub.7                                                                      H      H      CH.sub.3                                                                           N(CH.sub.3 ).sub.2                             19   C.sub.2 H.sub.5                                                                      C.sub.3 H.sub.7                                                                      H      H    NH.sub.2                                       20   CH.sub.3                                                                             H      H      CH.sub.3                                                                            ##STR18##                                     21   C.sub.2 H.sub.5                                                                      H      CH.sub.3                                                                             CH.sub.3                                                                            ##STR19##                                     22   C.sub.2 H.sub.5                                                                      CH.sub.3                                                                             H      CH.sub.3                                                                            ##STR20##                                     23   CH.sub.3                                                                             H      CH.sub.3                                                                             CH.sub.3                                                                            ##STR21##                                     24   C.sub.2 H.sub.5                                                                      H      H      CH.sub.3                                                                            ##STR22##                                     25   C.sub.2 H.sub.5                                                                      H      H      CH.sub.3                                                                           OCH.sub.3                                      26   CH.sub.3                                                                             H      H      CH.sub.3                                                                            ##STR23##                                     27   C.sub.4 H.sub.9                                                                      CH.sub.3                                                                             CH.sub.3                                                                             H                                                                                   ##STR24##                                     28   C.sub.2 H.sub.5                                                                      H      H      H                                                                                   ##STR25##                                     29   C.sub.2 H.sub.5                                                                      H      CH.sub.3                                                                             CH.sub.3                                                                            ##STR26##                                     30   C.sub.2 H.sub.5                                                                      H      H      CH.sub.3                                                                           NHCH.sub.2 N(CH.sub.3).sub.2                   31   CH.sub.3                                                                             H                                                                                     ##STR27##                                                                           CH.sub.3                                                                           NHCH.sub.2 CH.sub.2 N(C.sub.2 H.sub.5).sub.                                   2                                              32   C.sub.2 H.sub.5                                                                      H                                                                                     ##STR28##                                                                           H    NH.sub.2                                       33   H      H                                                                                     ##STR29##                                                                           CH.sub.3                                                                           NHC.sub.4 H.sub.9                              34   H      H      CH.sub.3                                                                             CH.sub.3                                                                           Br                                             35   C.sub.2 H.sub.5                                                                      H      H      CH.sub.3                                                                            ##STR30##                                     36   C.sub.2 H.sub.5                                                                      H      CH.sub.3                                                                             CH.sub.3                                                                            ##STR31##                                     37   C.sub.2 H.sub.5                                                                      H      H      CH.sub.3                                                                            ##STR32##                                     38   H      CH.sub.3                                                                             H      CH.sub.3                                                                           OCH.sub.2 CH.sub.2 N(C.sub.2 H.sub.5).sub.2                                   .                                              39   CH.sub.3                                                                             H      H      H    OCH.sub.2 N(CH.sub.3).sub.2                    40   C.sub.2 H.sub.5                                                                      H                                                                                     ##STR33##                                                                           CH.sub.3                                                                           OCH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub                                   .2                                             41   C.sub.2 H.sub.5                                                                      H      CH.sub.3                                                                             CH.sub.3                                                                           OCH.sub.2 CH.sub.2 CH.sub.2 N(C.sub.3                                         H.sub.7).sub.2                                 42   C.sub.3 H.sub.7                                                                      C.sub.2 H.sub.5                                                                      H      C.sub.2 H.sub.5                                                                    OCH.sub.2 CH.sub.2 N(CH.sub.3).sub.2           ______________________________________                                    

what is claimed is:
 1. A compound of the formula ##STR34## wherein R, R¹and R³ each is hydrogen or lower alkyl;R² is hydrogen, lower alkyl orphenyl; R⁴ is aziridinyl, pyrrolidino, piperidino, pyrazolyl orpiperazinyl, said heterocyclics being unsubstituted or substituted witha hydroxy-lower alkyl group or one or two lower alkyl groups;andphysiologically acceptable salts thereof.
 2. A compound as in claim 1wherein R⁴ is aziridinyl, pyrrolidino, piperidino, pyrazolyl orpiperazinyl.
 3. A compound as in claim 1 wherein R⁴ is piperazinyl.
 4. Acompound as in claim 1 wherein R⁴ is (lower alkyl)piperazinyl.
 5. Acompound as in claim 1 wherein R⁴ is piperidino.
 6. A compound as inclaim 1 wherein R, R¹, R² and R³ each is hydrogen or lower alkyl.
 7. Acompound as in claim 4 wherein R, R¹, R² and R³ each is hydrogen orlower alkyl.
 8. A compound as in claim 5 wherein R, R¹, R² and R³ eachis hydrogen or lower alkyl.
 9. A compound as in claim 1 wherein R isethyl, R¹ is hydrogen, R² and R³ each is methyl and R⁴ is(4-methyl-1-piperazinyl).
 10. A compound as in claim 5 wherein R isethyl, R¹ is hydrogen and R² and R³ each is methyl.